Pathophysiology of hemochromatosis. (A) Hepcidin production by hepatocytes is feedback-regulated by iron through complex multimolecular pathways. Interaction between BMPs (especially BMP2 and BMP6) produced by liver sinusoidal endothelial cells (LSEC) and BMP receptors 1-2 is the main pathway controlling basal hepcidin production. Hemojuvelin is a BMP coreceptor. High Fe (HFE) and transferrin receptor 2 (TFR2) participate in iron sensing and modulate the response to increased circulating iron. For a comprehensive review, see Galy et al.9 Mutations in heterogenous genes (red X) lead to hepcidin deficiency (B). Iron hyperabsorption and excess iron release from macrophages expand the plasma iron pool (blue arrows) with the formation of toxic non-transferrin-bound iron (NTBI), which accumulates in the liver and other organs. Fe, iron; RBC, red blood cell.